Patients with advanced stages of cancer frequently experience pain that can be difficult to manage with current therapeutic approaches. Recently developed models of cancer pain are beginning to unravel the mechanisms underlying interactions between tumor cells and the nervous system that may underlie this pain. Our preliminary studies show that innervation and vascularization of an osteolytic fibrosarcoma implanted into the hind paws of mice decrease with tumor growth. These changes occur as pain behaviors increase in this model. Our goal is to develop more effective approaches to treat cancer pain. One potential approach is the use of cannabinoids. Our studies using murine models of cancer pain suggest that acute administration cannabinoids attenuate tumor-evoked pain behaviors. However, chronic administration of cannabinoids can produce tolerance. This has been shown for the antinociceptive effects of cannabinoids in animal models of acute pain. Whether chronic administration of cannabinoids is effective or results in the development of tolerance in models of chronic pain has not been reported. Cannabinoids reduce proliferation of some tumor cell lines and decrease tumor growth in vivo. In some tumor cell lines, cannabinoids induce apoptosis. Therefore, chronic administration of cannabinoids may also decrease tumor growth and thereby the morphological changes in innervation and vascularization associated with tumor growth and tumor-evoked pain. We will use behavioral assays, computer modeling, immunohistochemistry, confocal microscopy, and stereological methods to determine whether chronic administration of the cannabinoid agonist, CP 55, 940, attenuates the development of tumor-evoked mechanical hyperalgesia, tumor growth, innervation and vascularization in a murine model of cancer pain. Positive results from these studies would suggest that cannabinoids could be useful for the treatment of cancer pain.